Activation of Ras signaling increases radiation survival in human tumor cells. The Ras pathway can be activated by mutation of the ras oncogene or by growth factor receptor amplification or mutation. Signaling through ras from upstream receptors may be as, or more important in cell survival after radiation and that there may be significant differences between the different species of Ras in that regard. Validation of this idea may have a very significant effect on clinical trial design. PI3-kinase is the down-stream effector of Ras signaling whose activation results in increased radiation survival. Activation of PI3-kinase can, by itself lead to increased radiation survival in cells in which Ras is not activated. Thus the pathway for radiation survival can initiate at the cell surface, at Ras, or through activation of PI3-kinase in a Ras-independent manner. Inhibiting PI3-kinase is therefore an attractive approach for radiosensitization. Since inhibition of all PI3 kinase signaling is likely to have significant toxicity, it is important to determine whether a single PI3-kinase, a subset from this family or all PI3-kinase members can transmit survival signals that promote tumor cell survival. This proposal will seek to determine whether specific inhibition of a single catalytic or regulatory subunit is sufficient to alter PI3-kinase mediated radiation resistance. The Akt/PKB kinases are involved in survival signaling and have been implicated in radiation survival. These kinases are activated by PI3-kinase and could pose an alternate target for radiosensitization. There are three Akt isoforms. We propose to determine whether Akt is involved in radiation survival and if so, to identify which of these are contributors to enhanced radiation survival in tumor cells. We will explore the elements downstream from AKT that are survival regulators. Finally we will initiate animal experiments aimed at examining whether inhibiting the Ras signal transduction pathway at Ras or at points other than Ras yields superior radiosensitization.